The work involves the synthesis and evaluation of compounds for use as potential iron-chelating drugs to treat patients with beta-thalassemia. Three related approaches are being undertaken. The first involves the design of an orally effective drug. The emphasis is on multidentate ligands containing 3-hydroxy-gamma-pyrone, pyridoxal, tropolone or thiosemicarbazone moieties with the latter two being of lesser importance. The second approach involves the preparation and testing of organ-specific chelators, particularly those that might be directed toward the heart as cardiac failure is responsible for the ultimate demise of most patients suffering from transfusional siderosis. Lastly, the role of a nonabsorbable intraluminal chelator in chelation therapy is being investigated. Such a chelator could serve two purposes. It might bind inorganic dietary iron and, hopefully, be able to unload iron from low molecular weight chelators acting via the enterohepatic circulation. The latter ligands could then be reused, thereby minimizing the amount of drug administered. Given the variable results that have been obtained thus far in the search for an orally effective iron-chelating drug, it would appear that a multifaceted approach to chelation therapy will probably be required.